The compounds of the Formula I are generally known to be tumor promoters and as being highly irritant to skin and the mucous membrane.
The preferred exemplar TPA is a biologically active natural compound which can be extracted from croton oil. TPA has been known for many years to be a co-carcinogen or tumor promoter. See Merck Index, 11th Edition, Page 1164 No. 7306. It is also known to be a highly potent irritant to skin and to be harmful if ingested orally. In a product brochure distributed by Chemsyn Science Laboratories of Lenexa, Kansas, TPA is described as an extremely potent mouse skin cancer promoter and as a powerful mitogen in cell cultures. The product brochure warns the user to treat TPA with extreme care. The literature discloses that TPA induces differentiation in the stable human promyelocytic leukemic cell line HL-60. Weinberg, JP (Science 213:655-657, 1981) further discloses that TPA causes differentiation of cells of the human leukemia cell line HL-60 to nondividing macrophage-like cells. These differentiated cells are cytotoxic for tumor cells including current, untreated HL-60 cells in vitro. However, nowhere in the prior art has it been suggested that compounds of the Formula I when delivered parenterally to humans would be effective in treating neoplastic diseases or in raising the white blood cell count, much less without significant unwanted side effects.
Leukemia is a neoplastic disease in which white corpuscle maturation is arrested at a primitive stage of cell development. The disease is characterized by an increased number of leukemic blast cells in the bone marrow and by varying degrees of failure to produce normal hematopoietic cells. The condition may be either acute or chronic. Leukemias are further typically characterized as being lymphocytic or myelocytic. Acute lymphocytic leukemia (ALL) arises in lymphoid tissues and ordinarily first manifests its presence in bone marrow. Acute myelocytic leukemia (AML) arises from bone marrow hematopoietic stem cells or their progeny. The term "acute myelocytic leukemia" subsumes several subtypes of leukemia e.g. myeloblastic leukemia, promyelocytic leukemia and myelomonocytic leukemia.
Chronic myelogenous leukemia is characterized by abnormal proliferation of immature granulocytes, for example, neutrophils, eosinophils and basophils, in the blood, bone marrow, the spleen, liver and sometimes in other tissues. A large portion of chronic myelogenous leukemia patients develop a transformation into a pattern indistinguishable from the acute form of the disease. This change is known as the "blast crises": The present invention is generally suitable for treating leukemias, as well as other neoplastic diseases.